EP1727797A1 - Verfahren zur kreuzkupplung von indolen - Google Patents

Verfahren zur kreuzkupplung von indolen

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Publication number
EP1727797A1
EP1727797A1 EP05724459A EP05724459A EP1727797A1 EP 1727797 A1 EP1727797 A1 EP 1727797A1 EP 05724459 A EP05724459 A EP 05724459A EP 05724459 A EP05724459 A EP 05724459A EP 1727797 A1 EP1727797 A1 EP 1727797A1
Authority
EP
European Patent Office
Prior art keywords
mixture
compound
alkyl
aryl
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP05724459A
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English (en)
French (fr)
Other versions
EP1727797B1 (de
Inventor
Ahmad Boehringer Ingelheim Pharm.Inc. KHODABOCUS
Guisheng Boehringer Ingelheim Pharm. Inc. LI
Zhi-Hui Boehringer Ingelheim Pharm. Inc. LU
Frank Boehringer Ingelheim Pharm.Inc. ROSCHANGAR
C.H. Boehringer Ingelheim Pharm. Inc. SENANAYAKE
Ming Boehringer Ingelheim Pharm. Inc. SHEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharmaceuticals Inc
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Application filed by Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharmaceuticals Inc
Publication of EP1727797A1 publication Critical patent/EP1727797A1/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to the field of pharmaceuticals and more specifically to processes for making 2, 3-disubstituted indoles.
  • Substituted indoles are useful as phannaceutical agents.
  • substituted indoles used as pharmaceutical agents and the preparation thereof include the anti- inflammatory agents indomethacin and tropesin, the antihistamine mebhydroline, and the vasodilator vinpocetine.
  • Other examples of indole compounds used as pharmaceutical agents are indole compounds such as disclosed in US patent application No. 10/198,384 (US2004/0024190) the contents of which are incorporated herein by reference and useful as HCV polymerase inhibitors in the treatment of HCV infections.
  • a convenient method for preparing aryl-substituted indoles is by a palladium catalyzed cross coupling reaction, such as for example Negishi cross coupling (E. Negishi, S. Baba, J. Chem. Soc. Chem. Communications, 1976, 596-597 ; S. Baba, E. Negishi, J. Am. Chem. Soc, 1976, 98, 6729- 6731), or Suzuki cross coupling (J. Hassan et al., Chem Rev., 2002, 102, 1359 and N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457).
  • Negishi cross coupling E. Negishi, S. Baba, J. Chem. Soc. Chem. Communications, 1976, 596-597 ; S. Baba, E. Negishi, J. Am. Chem. Soc, 1976, 98, 6729- 6731
  • Suzuki cross coupling J. Hassan et
  • Important variables often include, but are not limited to selection of metal catalysts, such as Pd, Ni, Pt etc, ligands, such as mono-dentate triphenylphosphine (Ph 3 P), tri-p-tolylphosphine (p-Tol 3 P), tricyclohexylphosphine
  • PCy 3 tri-t-butylphosphine (t-Bu 3 P), (Cy 2 P(Ph-Ph)) and bi-dentate 1,1'- bis(diphenylphosphino)ferrocene (dppf), l,4-bis(diphenylphosphino)ferrocene (dppb) etc., solvents, such as tetrahydrofuran (THF), dimethoxyethane (DME), dimethylformamide (DMF), l-methyl-2-pyrrolidinone (NMP) etc., and temperature and bases in the case of the Suzuki reaction such as K 2 C0 3 .
  • THF tetrahydrofuran
  • DME dimethoxyethane
  • DMF dimethylformamide
  • NMP l-methyl-2-pyrrolidinone
  • the present invention relates to processes for making 2, 3-disubstituted indoles. More specifically, the invention also provides for a process to make 2,3-disubstituted indoles disclosed in US patent application No. 10/198,384 and intermediates thereof.
  • L is Br or CI
  • R is H or C ⁇ - 8 alkyl
  • X is C -C 8 cycloalkyl, aryl or H, Ci - C 8 alkyl
  • Y is heteroaryl or aryl
  • Z is H, HO 2 C-, Ci-s alkyl 0 2 C-, C ⁇ - 6 alkyl HNC(O)-,
  • a metal catalyst selected from Pd, Ni, a ligand selected from Ph 3 P, / Tol 3 P, tri(2-furyl)phosphine, Cy 3 P, tBu 3 P, Cy 2 P(Ph-Ph), dppf and dppb, in a solvent selected from THF, DMF, NMP or a combination thereof, at a temperature of between ambient and 100°C, to provide the desired compound of formula I.
  • a metal catalyst selected from Pd, Ni, a ligand selected from Ph 3 P, / Tol 3 P, tri(2-furyl)phosphine, Cy 3 P, tBu 3 P, Cy 2 P(Ph-Ph), dppf and dppb
  • a solvent selected from THF, DMF, NMP or a combination thereof
  • Another aspect of the invention provides the process of the first embodiment wherein the ligand is either Ph 3 P, Cy 3 P or Cy 2 P(Ph-Ph).
  • Another aspect of the invention provides the process of the first embodiment wherein the solvent is a mixture of THF and NMP.
  • Another aspect of the invention provides the process of the first embodiment foi ⁇ making a compound of formula I as described above wherein L is Br or CI R is H or methyl; X is C 3 . C 8 cycloalkyl; Y is heteroaryl or aryl; Z is H, H0 2 C-, Ci. 8 alkyl0 2 C-,
  • Another aspect of the invention provides the process of the first embodiment for making a compound of formula I: wherein:
  • L is Br or CI
  • R is H or methyl
  • X is cyclopentyl Y is pyridyl L is Br or CI
  • Z is H, H0 2 C-, Ci- 8 alkyl0 2 C-, wherein Q is selected from:
  • L is Br or CI
  • R is H or methyl
  • Z is
  • X is cyclopentyl
  • Y is pyridyl
  • Another aspect of the invention provides the compound having the formula:
  • L is Br or CI
  • Another aspect of the invention provides for the compound having the formula:
  • L is Br or CI; and R is H or methyl.
  • aryl means a 6-12 membered aromatic caxbocycle, which can be a single ring or can be multiple rings fused together or linked covalently.
  • aryl includes, for example, phenyl and naphthyl; other terms comprising "aryl” will have the same definition for the aryl component, examples of these moieties include: arylalkyl, aryloxy or arylthio.
  • alkyl refers to a saturated aliphatic radical containing from one to ten carbon atoms or a mono- or polyunsaturated aliphatic hydrocarbon radical containing from two to twelve carbon atoms unless otherwise stated.
  • the mono- or polyunsaturated aliphatic hydrocarbon radical contaLns at least one double or triple bond, respectively.
  • Alkyl refers to both branched a-nd unbranched alkyl groups. Examples of “alkyl” include alkyl groups which are straight chain alkyl groups containing from one to eight carbon atoms and bran-ched alkyl groups containing from three to ten carbon atoms.
  • alkyl groups which are straight chain alkyl groups containing from one to s ix carbon atoms and branched alkyl groups containing from three to six carbon atoms.
  • alk or “alkyl” prefix refers to analogs according to the above definition of “alkyl”.
  • alkoxy alkoxy
  • alkythio refer to alkyl groups linked to a second group via an oxygen or sulfur atom.
  • Each alkyl or alkyl analog described herein shall be understood to be optionally, partially or fully halogenated.
  • cycloalkyl refers to the cyclic analog of " an alkyl group, as defined above.
  • examples of cycloalkyl groups are saturated or unsaturated nonaromatic cycloalkyl groups containing from three to eight carbon atoms, and other examples include cycloalkyl groups having three to six carbon atoms.
  • heteroaryl refers to a stable 5-8 memh>ered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical.
  • Each heterocycle consists of carbon atoms and from 1 to -4 heteroatoms chosen from nitrogen, oxygen and sulfur.
  • the heteroaryl group may be attached by any atom of the ring which results in the creation of a stable structure.
  • heteroaryl examples include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinn-olinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
  • cycloalkyl means that the cycloalkyl radical may or may not be substituted and that the description includes both substituted cycloalkyl radicals and cyckloalkyl radicals having no substitution.
  • substituted means that any one or more hydrogens on ant atom of a group or moiety, whether specifically designated or not, is replaced with a selection from the indicated group of substituents, provided that the atom's normal vale-ncy is not exceeded and that the substitution results in a stable compound.
  • the preferred solvents are DMSO, DMF, DMAC, DMA, NMP, N-ethyl pyrrolidinone, l,3-dimethyl-2-imidazolidinone.
  • the most preferred solvent is NMP.
  • the preferred combination of solvents is NMP-THF (2:1).
  • the temperature was also found to impact the cross coupling reaction of the present invention. For example the reaction took over 24 hours to complete at 70 °C, while it only took 3 hours at 90°C.
  • the preferred temperature is between 70 and 90°C.
  • the present invention discloses a method that can be used for the production of cross coupled indole compounds on a large scale (25kg), by coupling of a 2-bromoindole with an aryl or heteroaryl zinc species intermediate.
  • One embodiment of the invention provides a method for making tri-substituted indoles such as 3-cyclopentyl-6- methoxycarbonyl-2-(2-pyridyl)indole by coupling of l-methyl-2-bromo-3- cyclopentyl-6-methoxycarbonyl indole with either 2-pyridylzinc bromide or di(2- pyridyl)zinc (Scheme II).
  • the 2-chloro indole intermediate can be used in a palladium catalyzed cross coupling of aryl chlorides as shown in Scheme III.
  • the cost for aryl chlorides is often significantly lower than the corresponding bromo or iodo analog.
  • this present invention provides an economical route to generate a variety of 2, 3-disubstituted indole compounds with important medicinal value.
  • reaction mixture After cooling to 35 - 40 °C, the reaction mixture was charged with 3046 g of NMP, followed by addition of 202.4 g (1.487 mol, 1.0) of methyl benzoate. The reaction mixture was warmed to 65 °C for another lh, then cooled to 35 °C. To the mixture was added sequentially 6.66 g (0.029 mol, 0.02 eq) of palladium acetate, 31.14 g (0.119 mol, 0.08 eq) of PPh 3 and 500.0 g (1.487 mol, 1.0 eq) of 2-bromo-3-cyclopentyl-l-methyl-lH-indole- carboxylic acid methyl ester.
  • reaction mixture was warmed to 70 °C over lh, then warmed to 90 °C and stirred at 90 °C for 3h.
  • 25.2 g (0.124 mol, 0.083 eq) of tributyl phosphine, 2600 g of isopropyl acetate, and 3270 g of saturated ammonium solution were added sequentially to the reaction mixture.
  • the batch contents were filtered and the solid was washed with 2 x 670 g of isopropyl acetate.
  • the organic phase was separated, washed with 2 x 2230 g of 10% aq. NH 4 C1, and then treated with 1484 ml of 4 M aq. HC1.
  • the lower aq. phase was separated and the organic layer was extracted two times with 744 ml of 4 M aq. HC1.
  • the aqueous phases were combined followed by the addition then 602 g of 1-propanol and 0.2176 g (16.32 mol, 11.0 eq) of 50% sodium hydroxide were added.
  • the resultant mixture was heated to 89°C for 2h until the hydrolysis reaction was completed.
  • the mixture was cooled to 25°C and filtered through 0.5 micron inline filter. To the filtrate was added 322 g (5.36 mol, 3.6 eq) of acetic acid. After warming at 60°C for 1 h, the mixture was cooled to 25°C over 2 h.
  • the p ⁇ of the mixture was adjusted to 4-5 using 4 ⁇ C1 ( ⁇ 3 mL) and the mixture was stirred at 60 °C for 5 minutes and then transferred to a separatory funnel.
  • the aqueous layer was separated and extracted with isopropyl acetate (20 mL) at 60 °C.
  • the combined organic phases were washed with a mixture of saturated ammonium chloride (10 mL) and water (10 mL) at 60 °C.
  • the organic layer was extracted with 4 N ⁇ C1 (15 and 10 mL).
  • To the combined extracts cooled in an ice-water bath was slowly added 50% NaO ⁇ (9.40 g, 117.5 mmol). The mixture was heated to reflux until the batch inside temperature reached 89-90 °C.
  • n-Propanol (10 mL) was added and the mixture was stirred at 90 °C for 1 h.
  • acetic acid (1.57 g, 26.1 mmol) was slowly added to adjust the pH to 5-6.
  • the resulting white suspension was stirred at 60 °C for 1 h and allowed to cool to room temperature in 2 h.
  • the white precipitate was collected by filtration and the wet cake was rinsed with 2: 1 water/n-propanol (15 mL) and water (50 mL). The solid was dried under vacuum until a constant weight (2.67 g, 74 %). !
  • the suspension was brought to reflux for 0.5 h and then allowed to cool to room temperature in no less than 1 h.
  • the solid was collected by filtration, washed by 1 : 1 water/n-propanol (100 mL) and water (200 mL).
  • the l-[(2-bromo-3-cyclopentyl-l- methyl-lH-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid, obtained as a white solid was dried under vacuum until constant weight (17.78 g, 97%).
  • the aqueous layer was separated and extracted with isopropyl acetate (20 mL) at 60 °C.
  • the combined organic phases were combined and washed with a mixture of saturated ammonium chloride (10 mL) and water (10 mL) at 60 °C.
  • the organic layer was extracted with 4 N ⁇ C1 (10 and 5 mL).
  • 50% NaO ⁇ 5.60 g, 70 mmol.
  • the mixture was heated to reflux until the internal temperature reached 89-90 °C.
  • the mixture was cooled to 60 °C and n-propanol (10 mL) was added.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP05724459A 2004-03-08 2005-03-07 Verfahren zur kreuzkupplung von indolen Active EP1727797B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US55110704P 2004-03-08 2004-03-08
PCT/US2005/006919 WO2005092855A1 (en) 2004-03-08 2005-03-07 Process for cross coupling indoles

Publications (2)

Publication Number Publication Date
EP1727797A1 true EP1727797A1 (de) 2006-12-06
EP1727797B1 EP1727797B1 (de) 2012-05-30

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Country Status (14)

Country Link
US (1) US7332614B2 (de)
EP (1) EP1727797B1 (de)
JP (2) JP5442949B2 (de)
KR (1) KR20060128045A (de)
CN (1) CN1930124A (de)
AU (1) AU2005227289B2 (de)
BR (1) BRPI0508505A (de)
CA (1) CA2552980A1 (de)
IL (1) IL177936A0 (de)
NZ (1) NZ550177A (de)
RU (1) RU2430916C2 (de)
TW (1) TW200631939A (de)
WO (1) WO2005092855A1 (de)
ZA (1) ZA200605150B (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2335700A1 (de) 2001-07-25 2011-06-22 Boehringer Ingelheim (Canada) Ltd. Hepatitis C Virus Polymerase Inhibitoren mit heterobicylischer Struktur
US7098231B2 (en) * 2003-01-22 2006-08-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7223785B2 (en) 2003-01-22 2007-05-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
TWI368507B (en) * 2004-02-20 2012-07-21 Boehringer Ingelheim Int Viral polymerase inhibitors
AU2005227289B2 (en) * 2004-03-08 2012-03-08 Boehringer Ingelheim Pharmaceuticals, Inc. Process for cross coupling indoles
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
KR20070112165A (ko) * 2005-02-11 2007-11-22 베링거 인겔하임 인터내셔날 게엠베하 2,3-이치환된 인돌의 제조방법
US8076365B2 (en) * 2005-08-12 2011-12-13 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
AR072297A1 (es) 2008-06-27 2010-08-18 Novartis Ag Derivados de indol-2-il-piridin-3-ilo, composicion farmaceutica que los comprende y su uso en medicamentos para el tratamiento de enfermedades mediadas por la sintasa aldosterona.

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2335700A1 (de) * 2001-07-25 2011-06-22 Boehringer Ingelheim (Canada) Ltd. Hepatitis C Virus Polymerase Inhibitoren mit heterobicylischer Struktur
GB0323845D0 (en) * 2003-10-10 2003-11-12 Angeletti P Ist Richerche Bio Chemical compounds,compositions and uses
AU2005227289B2 (en) * 2004-03-08 2012-03-08 Boehringer Ingelheim Pharmaceuticals, Inc. Process for cross coupling indoles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005092855A1 *

Also Published As

Publication number Publication date
US20050234242A1 (en) 2005-10-20
CN1930124A (zh) 2007-03-14
KR20060128045A (ko) 2006-12-13
JP5442949B2 (ja) 2014-03-19
WO2005092855A1 (en) 2005-10-06
AU2005227289A1 (en) 2005-10-06
RU2006135543A (ru) 2008-04-20
TW200631939A (en) 2006-09-16
RU2430916C2 (ru) 2011-10-10
JP2011241217A (ja) 2011-12-01
EP1727797B1 (de) 2012-05-30
JP2007527906A (ja) 2007-10-04
US7332614B2 (en) 2008-02-19
BRPI0508505A (pt) 2007-07-31
AU2005227289B2 (en) 2012-03-08
NZ550177A (en) 2010-08-27
IL177936A0 (en) 2006-12-31
CA2552980A1 (en) 2005-10-06
ZA200605150B (en) 2007-10-31

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